Hemophilia B

GENERAL PRINCIPLES

Definition

Hemophilia B is an X-linked recessive coagulation disorder secondary to mutations in the gene encoding factor IX.

Epidemiology

Hemophilia B affects ~1 in 30,000 male births.

DIAGNOSIS

Clinical Presentation

Hemophilia B remains clinically indistinguishable from hemophilia A.

Diagnostic Testing

Factor IX activity. Hemophilia A (Factor VIII) and B (Factor IX) use the same severity scale based on degree of decreased factor activity.

TREATMENT

Therapy of hemophilia B consists of factor IX replacement with either plasma-derived factor IX or recombinant factor IX (BeneFIX).

• DDAVP lacks efficacy because it does not increase factor IX levels.

• Postinfusion peak targets, duration of therapy, and laboratory monitoring for treatment of hemophilia B- related bleeding are similar to those for hemophilia A.

• Every 1 IU/kg of factor IX replacement typically raises plasma factor IX activity by 1%. Standard Factor IX has a half-life of 18-24 hours.

• Extended factor IX products significantly prolonged the half-life by 4-6-fold, with half-life of 80-100 hours, allowing significant reduction of frequency in prophylactic factor infusion to 1-2 times a week.³⁷

• Gene therapy for factor IX deficiency has been more successfully than for factor VIII deficiency but remains only available under clinical research setting.

Complications of Hemophilia A and B Therapy

Inhibitors

• Alloantibodies to factors VIII and IX in response to replacement therapy develop in approximately 20% and 12% of severe hemophilia A and B patients, respectively. These alloantibodies neutralize infused factor VIII or IX.

• Determining the titer of a factor VIII or IX inhibitor, using a laboratory assay that reports inhibitor strength in Bethesda units (BUs), predicts inhibitor behavior and guides therapy.

• Treatment options for factor VIII or IX inhibitors include³⁸:

î Large doses of factor VIII or IX concentrates overcome inhibitors for patients with low titer (BU lt; 5).

î Because factor VIII or IX concentrates will not overcome inhibitors in patients with high titers (BU gt; 5), bypassing agents such as rFVIIa or activated prothrombin complex concentrate (aPCC) are used.³⁹

#9632; rFVIIa (NovoSeven) is dosed at 90 #956;g#8725;kg every 2 hours until hemostasis occurs.

#9632; aPCC (most commonly used-Factor Eight Inhibitor Bypassing Activity [FEIBA]), dosed at 75­100 IU/kg q12h. FEIBA contains activated factors VII, VIII, XI, X, and thrombin, and it can cause thrombosis or DIC.

• Emicizumab given as weekly subcutaneous injections and reduces annualized bleeding rate by 80%- 90% in hemophilia A patients with inhibitors and is FDA-approved for this population.⁴⁰ Subsequently, emicizumab was studied in patients without inhibitors and now is FDA-approved for patients with and without factor VIII inhibitors.⁴¹ Thrombotic microangiopathy is a rare complication in patients receiving concurrent aPCC.